Alzheimer’s disease can trick the brain into erasing its own memories

Much less certain remains how this destruction begins. One main explanation focuses on amyloid beta, a protein fragment that can accumulate in the brain and damage neurons. But researchers have also linked Alzheimer’s disease to many other factors, including tau proteins, lysosomes, chronic inflammation, immune cells called microglia, and other biological processes.

A possible connection between the two main theories

Scientists now believe they may have found a way to link two of the most important ideas about how Alzheimer’s develops. In a study published in Proceedings of the National Academy of Sciencesresearchers report new evidence that amyloid beta and inflammation may act through the same molecular pathway. Both appear to converge on a specific receptor that signals neurons when to remove synapses, the contact points that allow brain cells to communicate.

The research was led by Wu Tsai Neurosciences Institute affiliate Carla Shatz, Sapp Family Provostial Professor, along with first author Barbara Brott, a research scientist in Shatz’s lab. The work was partially supported by a Catalyst Award from the Knight Initiative for Brain Resilience, a program aimed at rethinking the basic biology behind neurodegenerative diseases such as Alzheimer’s.

Role of the synaptic pruning receptor

One major part of the study builds on earlier work involving a receptor known as LilrB2. Shatz studied this molecule for years. In 2006, she and her colleagues discovered that a mouse version of LilrB2 plays a critical role in synaptic pruning, a normal process during brain development and learning in adulthood.

Later findings linked this same receptor to Alzheimer’s disease. In 2013, Shatz’s team showed that amyloid beta can bind to LilrB2. When this happens, neurons are triggered to remove synapses. Importantly, the experiments also showed that removing the receptor genetically protected mice from memory loss in a model of Alzheimer’s disease.

Inflammation and the complement cascade

A second major line of research has investigated the immune process known as the complement cascade. Under healthy conditions, this system releases molecules that help the body eliminate viruses, bacteria and damaged cells.

However, inflammation is a well-known risk factor for Alzheimer’s disease. Recent studies increasingly link the complement cascade to excessive synaptic pruning and neurological disorders. These findings led Shatz to question whether molecules involved in inflammation might interact with LilrB2 in the same way as amyloid beta.

Testing a new hypothesis

To investigate this possibility, the research team examined molecules of the complement cascade to see if any could bind to the LilrB2 receptor. Only one molecule fits. The C4d protein fragment bound strongly enough to raise the possibility that it could directly contribute to synapse loss.

The scientists then tested this idea on live animals. They injected C4d into the brains of healthy mice to observe the effects. “Lo and behold, it took the synapses off the neurons,” Shatz said—quite a surprise for a molecule that researchers previously thought had no function at all.

A shared path to memory loss

Taken together, these findings suggest that both amyloid beta and inflammation may drive synapse loss through the same biological mechanism. This raises the possibility that scientists may need to rethink how Alzheimer’s causes memory to fade.

“There’s a whole set of molecules and pathways that go from inflammation to synapse loss that maybe haven’t gotten the attention they deserve,” said Shatz, who is also a professor of biology in the School of Humanities and Sciences and of neurobiology in the School of Medicine.

Neurons as active participants

The results also challenge a widely held assumption in Alzheimer’s disease research. Many scientists believed that glial cells, the brain’s immune cells, were primarily responsible for eliminating synapses in disease. This study suggests that the neurons themselves play a more direct role.

“Neurons are not innocent bystanders,” Shatz said. “They are active participants.”

Implications for the treatment of Alzheimer’s disease

This finding could have important implications for future therapies. Currently, the only FDA-approved treatment for Alzheimer’s disease aims to break up amyloid plaques in the brain. According to Shatz, these drugs have brought limited benefits and significant risks.

“Breaking up the amyloid plaques hasn’t worked as well, and there are a lot of side effects,” such as headaches and bleeding in the brain, Shatz said. “And even if they work well, you’re only solving part of the problem.”

A more effective approach may involve targeting receptors such as LilrB2 that directly control synapse removal. By protecting synapses, Shatz said, it may be possible to preserve memory itself.

Study authors and funding

The study was written by Barbara Brott, Aram Raissi, Monique Mendes, Caroline Baccus, Jolie Huang, and Carla Shatz of Stanford University’s Department of Biology, Stanford Medicine’s Department of Neurobiology, and Bio-X; Kristina Micheva of Stanford’s Department of Molecular and Cellular Physiology; and Jost Vielmetter of the California Institute of Technology.

Financial support came from the National Institutes of Health (1R01AG065206 and 1R01EY02858), the Sapp Family Foundation, the Champalimaud Foundation, the Harold and Leila Y. Mathers Charitable Foundation, the Ruth K. Broad Biomedical Research Foundation, and the Phil and Penny Knight Initiative for Brain Wu. University Resilience Institute at Brain Wu’s Neuross Institute. Human Alzheimer’s disease tissue samples were provided by the Neurodegenerative Disease Brain Bank at the University of California, San Francisco, which receives funding from the NIH (P01AG019724 and P50AG023501), the Frontotemporal Dementia Research Consortium, and the Tau Consortium.